Extensive peripheral immune cell phenotypes and nephrotic syndrome: Tracing causality through genetics – a bilateral Mendelian randomization study

Nephrotic syndrome (NS) is a complex renal disorder characterized by significant proteinuria, hypoalbuminemia, and hyperlipidemia. While its etiology involves genetic and environmental factors, the role of the immune system in NS's pathogenesis remains incompletely understood. We adopted a bilateral Mendelian randomization approach, leveraging genetic variations as proxies to explore the causality between immune cell traits and NS. Utilizing genetic data sourced from the genome-wide association studies Catalog and FinnGen's database, we analyzed the association of 731 immune phenotypes with NS. Instrumental variables were selected based on stringent criteria, and the analysis was augmented by the inverse-variance weighting method, alongside sensitivity analyses to assess the robustness of our findings. Our analysis identified a significant causal association between CD8br natural killer T cell absolute cell count and NS, suggesting a novel immune-related risk factor for NS. In addition, decreased levels of 8 kinds of regulatory T cell phenotypes were observed in NS onset, suggesting a broader immunological impact of NS. These findings were supported by sensitivity analyses, which confirmed the stability and validity of the identified causal relationships. This pioneering study highlights the significant role of specific immune cell traits in the pathogenesis of NS, offering new insights into its immunopathological mechanisms. Future research should aim to elucidate the biological mechanisms underlying these associations and explore their implications across diverse populations to enhance the generalizability and applicability of these insights.